Effect of 3 Months of Antimicrobial Treatment WithClarithromycin in Acute Non–Q-Wave Coronary Syndrome

Juha Sinisalo, MD; Kimmo Mattila, MD; Ville Valtonen, MD; Olli Anttonen, MD;Jukka Juvonen, MD; John Melin, MD; Helena Vuorinen-Markkola, MD; Markku S. Nieminen, MD;for the Clarithromycin in Acute Coronary Syndrome Patients in Finland (CLARIFY) Study Group

Background—Coronary artery disease, an inflammatory disease, may be caused by infection. We investigated whether theantibiotic clarithromycin would reduce morbidity and mortality in patients with acute non–Q-wave coronary syndrome.

Methods and Results—Altogether, 148 patients with acute non–Q-wave infarction or unstable angina were randomlyassigned to receive double-blind treatment with either clarithromycin or placebo for 3 months. The primary end pointwas a composite of death, myocardial infarction, or unstable angina during treatment; the secondary end point wasoccurrence of any cardiovascular event during the entire follow-up period (average 555 days, range 138 to 924 days).There was a trend toward fewer patients meeting primary end-point criteria in the clarithromycin group than in theplacebo group (11 versus 19 patients, respectively; risk ratio 0.54, 95% CI 0.25 to 1.14; P�0.10). By the end of theentire follow-up, 16 patients in the clarithromycin group and 27 in the placebo group had experienced a cardiovascularevent (risk ratio 0.49, 95% CI 0.26 to 0.92; P�0.03).

Conclusions—Clarithromycin appears to reduce the risk of ischemic cardiovascular events in patients presenting withacute non–Q-wave infarction or unstable angina. No signs of this effect diminishing were observed during follow-up.(Circulation. 2002;105:1555-1560.)

Key Words: angina � coronary disease � infection

Myocardial infarction and unstable angina derive frominflammation, which causes plaque vulnerability.1 In-

creasing attention has recently been paid to infections as oneof the causes of inflammation.2 Seroepidemiological, his-topathological, and clinical studies in humans and animalshave shown that several infections are associated with coro-nary artery disease (CAD).3–5

Because only a few studies of antibiotic use in CADpatients have been published, the effect of treatment ofinfections on the prognosis of CAD is unclear.6–9 Further-more, studies of patients with stable CAD have given dis-crepant results.6,8 This may be due to the magnitude ofinflammation being different in patients with stable versusunstable CAD.10 Patients with acute coronary syndromesappeared to benefit from a 1-month treatment with a macro-lide antibiotic; however, the treatment advantage was lost in6 months.11 We studied the effect of a 3-month clarithromy-cin treatment on cardiovascular events in patients who pre-sented with acute non–Q-wave infarction or unstable anginapectoris.

MethodsWe conducted a randomized, double-blind, placebo-controlled studyof patients with unstable angina or non–Q-wave myocardial infarc-

tion. The patients were recruited between September 1998 andDecember 2000 from 9 hospitals in different parts of Finland. Theethics committees of the participating hospitals approved the study,and all patients gave written informed consent.

PatientsPatients of either sex aged 18 to 80 years who entered the hospitalwith prolonged chest pain together with clearly documented ST-T-wave changes indicating either unstable angina or non–Q-wavemyocardial infarction were eligible for the study. Patients must havehad an episode of angina within the 48 hours preceding randomiza-tion and presented with at least 1 of the following clinical entities ofanginal pain: (1) accelerating pattern, (2) prolonged (�20 minutes)pain with minimal effort, of (3) pain with minimal exertion (�20minutes) occurring �48 hours after an acute Q-wave myocardialinfarction. Patients also had to have ECG evidence of myocardialischemia: (1) new, persistent, or transient ST-segment depression�0.1 mV (0.08 seconds after the J-point) in at least 2 extremity leadsor 3 precordial leads; (2) transient (�20 minutes) ST-segmentelevation �0.1 mV in at least 2 extremity leads or 3 precordial leads;or (3) new or transient T-wave inversion �0.3 mV in at least 3extremity leads or 3 precordial leads (excluding V1). Patients whomet the anginal pain inclusion criteria but none of the ECG criteriawere eligible to enter the trial if their creatine kinase-MB mass,creatine kinase-B, troponin-T, or troponin-I fraction at the time ofenrollment was consistent with the occurrence of myocardialinfarction.

Exclusion criteria were thrombolysis within the previous 48 hours;coronary angioplasty within 6 months or CABG within 3 months, or

Received October 23, 2001; revision received January 28, 2002; accepted January 28, 2002.From Helsinki University Central Hospital, Department of Medicine, Division of Cardiology (J.S., H.V.-M., M.S.N.), and Infectious Diseases (K.M.,

V.V.), Helsinki; Lahti Central Hospital (O.A.), Lahti; Kajaani Central Hospital (J.J.), Kajaani; and Jyväskylä Central Hospital (J.M.), Jyvaskyla, Finland.Correspondence to Juha Sinisalo, MD, Helsinki University Central Hospital, PO Box 340, FIN-00290 Helsinki, Finland. E-mail juha.sinisalo@hus.fi© 2002 American Heart Association, Inc.

Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000012544.07696.1F

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these procedures already planned; angina precipitated by obviousprovoking factors (eg, tachycardia); ST-T-segment elevation (�20minutes); inability to interpret ST-T-segment changes on ECG; longQTc (�470 ms); severe renal or hepatic failure; and ongoingantibiotic therapy of any duration.

Randomization, Treatment, and Follow-UpRandomization was done separately in each participating center.Randomization lists were based on a table of random numbers,12 andan independent hospital pharmacist of Helsinki University CentralHospital assigned patient numbers for each center (in blocks of 6)and delivered study medication.

Patients received one 500-mg clarithromycin tablet (Klacid 500mg OD, Abbott Laboratories) or a matching placebo once daily for85 days. The randomization codes were sealed in closed envelopes,which could be opened only if considered necessary for the treatmentof severe adverse events.

The study treatment was in addition to patients’ normal antiangi-nal medication, which typically consisted of aspirin, �-blocker,nitrate, and low-molecular-weight heparin. The choice of this med-ical therapy and the decision to perform coronary angiography andrevascularization, if indicated, was left to the discretion of thetreating physician. Revascularization (PTCA, stenting, or CABG)was not considered an end point, but study medication was discon-tinued for the duration of this procedure. If off-protocol antibioticswere necessary, the study medication was discontinued for thecourse and reintroduced thereafter.

Medical history was taken and physical examination, laboratoryevaluation, and ECG recording were performed at randomization andat the second (days 5 to 8, usually on the day of discharge), third(days 85 to 95; end of study medication), and fourth (day 365�15)visits. Thereafter, information about the defined end points wasobtained from hospital records and telephone inquiry. Baselinecharacteristics were taken from patients’ medical histories. Treat-ment compliance was assessed by pill count.

End PointsThe primary end point was occurrence of the composite of death ofany cause, myocardial infarction, or unstable angina within the3-month treatment period. Originally, the secondary end point wasoccurrence of the same composite of end points as in the primarygrouping plus ischemic strokes within 1 year after randomization.Because the targeted number of patients could not be reached (seeStatistical Analyses), it was decided to include all cardiovascularevents (death, myocardial infarction, unstable angina, ischemicstroke, or critical peripheral ischemia [demanding operation]) occur-ring during the entire follow-up (to the end of April 2001) in thesecondary-end-point grouping. Myocardial infarction after random-ization was defined as a new episode of chest pain, with new Q-wave(�0.03 second in duration in 2 or more leads), or both, and elevatedcardiac enzyme levels consistent with occurrence of myocardialinfarction.

After randomization but during the initial hospital stay, unstableangina was defined as stated in inclusion criteria. However, this newepisode had to lead to some additional intervention, such asthrombolytic therapy or revascularization. After discharge frominitial hospitalization, unstable angina was also defined as in theinclusion criteria, but here the patient had to be rehospitalized for atleast 24 hours.

Two cardiologists (J.S., M.S.N.) examined all patient files todetermine whether the cardiovascular events recorded fulfilled cri-teria of either primary or secondary end points. This was done beforethe treatment code was opened.

Patient Populations FormedPatients were eligible for the intention-to-treat population if theyfulfilled all inclusion criteria and none of the exclusion criteria, weresuccessfully randomized, and took at least 1 tablet of study medica-tion and if information about occurrence of end points was availableuntil the end of follow-up.

Statistical AnalysesClinical event rate estimates were based on the ROXIS pilot study,7

which reported a reduction in events from 9% to 2% in 1 month. Ifa placebo event rate of 20% is assumed,13,14 100 patients per groupprovided �90% power to detect a decrease from 20% to 4% withactive treatment using a 2-sided alpha of 0.05.12

The recruitment of patients who matched our inclusion criteriaproved difficult. It was therefore decided to extend the follow-upuntil the end of April 2001 and to include all cardiovascular eventsas secondary end points. The treatment code was opened only afterall patients had completed the entire 3-month treatment, all datachecking had been done, and all cardiovascular events reported hadbeen evaluated with regard to meeting or not meeting end-pointcriteria.

Proportions were compared with �2 test or Fisher’s exact test, andquantitative data were compared with t test or Mann-Whitney test.Kaplan-Meier curves were produced to describe event-free survival,and the difference between groups was analyzed with the log-ranktest.

The independent contribution of the potential determinants ofevent-free survival was analyzed with the Cox model, with theoccurrence of an end point as the dependent variable and thetreatment code and other potential determinants (age, smoking, sex,diabetes, body mass index, hypercholesterolemia, and hypertension)as independent variables. The risk ratios and their 95% CIs were alsoobtained from the Cox model. All calculations were made on anintention-to-treat basis with the SPSS 10.0 statistical package (SPSSInc).

ResultsPatientsA total of 152 patients were randomized. Of these, 4 wereexcluded; 148 patients (74 in each group) started the medi-cation (Figure 1).

Baseline characteristics of the 2 study groups are given inTable 1. The groups were well balanced with regard todemographic features, cardiovascular risk factors, previoustreatment procedures, and medications. All patients werewhite. The reason for inclusion was non–Q-wave infarctionfor 69% and 73% of the patients in placebo and clarithromy-cin groups, respectively; the rest of the patients had unstableangina (P�NS between groups).

Figure 1. Patient recruitment. *All patients alive returned for3-month visit.

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Overall, 41% of the patients used statins at the time of thefirst visit (Table 1). At the 1-year visit, the rate had increasedto 75% in the placebo group and 65% in the clarithromycingroup (P�NS). Aspirin was used by 95% of patients in bothgroups at the first visit. At the 1-year visit, the frequency waslower but still similar in both groups: 79% in the placebogroup and 90% in the clarithromycin group (P�NS).

The use of ACE inhibitors and angiotensin II receptorantagonists was low, with �20% of patients using eitherthroughout the study; no significant differences betweengroups were observed. The use of �-blockers was common,with 85% of patients using them similarly in both groupsthroughout the trial.

No significant differences were found between groupsregarding the use of off-study antibiotics (Table 2). In mostcases, the antibiotic was used as a prophylactic for CABG

(usually 1 dose of cephalosporin, with or without vancomy-cin). The use of off-study antibiotics had no influence onresults.

Treatment Compliance and Study WithdrawalsOf the patients, 55 (75% of survivors) in the placebo groupand 57 (77% of survivors) in the clarithromycin group took atleast 80% of the study medication (P�NS between groups).No patients were lost during the follow-up, but 14 patientsrefused to come to the 1-year visit; they were interviewed byphone. The hospital records of all patients were available forend-point analysis.

Outcome VariablesThe event rates during the 3-month medication period and theentire follow-up are presented in Table 3.

Primary End PointDuring the first 3 months, a trend was seen toward eventsoccurring less frequently in patients treated with clarithromy-cin compared with placebo (11 versus 19 patients; risk ratio0.54, 95% CI 0.25 to 1.14; P�0.10).

Secondary End PointWhen all cardiovascular events throughout the follow-up(median 555 days) were included, clarithromycin signifi-cantly reduced the rate of cardiovascular events. Sixteenpatients in the clarithromycin group and 27 in the placebogroup met end-point criteria (risk ratio 0.49, 95% CI 0.26 to0.92; P�0.03). There were 4 deaths in the clarithromycingroup, all caused by ischemic heart disease, and 1 death in theplacebo group caused by cancer (which was not considered acardiovascular end point). In subgroup analyses, the greatestdifference in the number of end points between groups wasobserved in myocardial infarctions, with 5 and 14 patientsexperiencing myocardial infarctions in the clarithromycin andplacebo groups, respectively. Unstable angina occurred in 5and 11 patients, respectively. Strokes were more rare; only 2patients met this end point in both groups. No peripheralcritical ischemia was observed during the trial.

The event-free survival curves (Figure 2) show that the 2treatment groups started to separate during the first 3 months,and the difference between them increased up to �300 days,remaining approximately the same thereafter. The reductionin the relative risk of events offered by clarithromycin was41%. The absolute risk reduction was 14.9%, which indicatesthat 7 patients would need to be treated to prevent 1cardiovascular event during the follow-up.

TABLE 1. Baseline Characteristics of Patients

Clarithromycin(n�74)

Placebo(n�74) P

Age, y 64�10 63�11 0.63

Women 22 (30) 26 (35) 0.59

Body mass index, kg/m2 27.0�3.8 27.1�3.9 0.8

Inclusion in trial

Inclusion by unstable angina 20 (27) 23 (31) 0.72

Inclusion by non–Q-wave infarction 54 (73) 51 (69) 0.72

Clinical history

Hypertension 35 (47) 27 (36) 0.24

Diabetes 16 (22) 12 (16) 0.53

Hypercholesterolemia 58 (78) 55 (74) 0.7

Previous myocardial infarction 18 (24) 18 (24) 1

Previous PTCA 1 (1) 3 (4) 0.62

Previous CABG 6 (8) 11 (15) 0.3

Smoking status 0.45

Current 19 (26) 21 (28)

Ex-smoker 26 (35) 19 (26)

Never 29 (39) 34 (46)

Medication at baseline

Aspirin 72 (97) 69 (93) 0.44

�-Blockers 60 (81) 66 (89) 0.25

ACE inhibitor or AT II blocker 15 (20) 14 (19) 1

Statins 29 (39) 32 (43) 0.74

AT indicates angiotensin.Values are mean�SD or n (%).

TABLE 2. Off-Study Antibiotic Use

Clarithromycin Placebo

Total No. Antibiotics (No. of Patients) Total No. Antibiotics (No. of Patients)

Before entry 4 Q (1), S (1), M (1), P (1) 5 T (2), P (3)

During 3-month treatment 16 pr (9), P (4), M (1), Q (1),T (1)

20 pr (10), Q (2), S (2), P (4),M (1), U (1)

After 3-month treatment 9 pr (6), P (2), M (1) 15 pr (9), P (5), S (1)

P indicates penicillin; T, tetracycline; Q, quinolone; M, macrolide; S, sulpha plus trimethoprim; U, unknownantibiotic; pr, prophylactic used for CABG (usually 1 dose of cephalosporin, with or without vancomycin).

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Coronary angiography was performed in 62% of all pa-tients (72% in the placebo group and 53% in the clarithro-mycin group, P�0.02 between groups), a finding consistentwith the higher incidence of end points in the placebo group.During the first 3 months, significantly fewer revasculariza-tions occurred in the clarithromycin group than in the placebogroup (17 versus 26 patients; risk ratio 0.54, 95% CI 0.291 to0.997; P�0.05). A similar finding was made during follow-up, with the corresponding figures being 27 and 38 patients(risk ratio 0.58, 95% CI 0.35 to 0.95; P�0.03). Detailedanalyses of revascularizations are shown in Table 4.

Adverse events (excluding deaths) were reported in 31patients: 18 in the placebo group (liver enzyme rise [10patients], allergic skin reaction [1], diarrhea [2], stomach

pains [1], headache [1], fever [1], long-QTc [1], and wors-ening of asthma [1]) and 13 in the clarithromycin group (liverenzyme rise [11], allergic skin reaction [1], and supraventric-ular arrhythmia [1]; P�0.41 between groups). None of theadverse events were classified as serious, but 19 patientsdiscontinued study medication. Premature opening of treat-ment codes was not necessary for any patient.

DiscussionThe results of this CLARIFY (Clarithromycin in AcuteCoronary Syndrome Patients in Finland) study suggest that 3months’ treatment with clarithromycin may reduce cardiovas-cular events in patients who present with acute unstableangina or non–Q-wave myocardial infarction. Clarithromycinreduced the risk of events by 41% during an averagefollow-up of 555 days. The shapes of the event-free survival

TABLE 3. Cardiovascular Events in Patients Undergoing Treatment

Clarithomycin(n�74)

Placebo(n�74)

Cox RegressionRR (95% CI) P * P†

3-Month treatment

Composite end point 11 (15%) 19 (26%) 0.54 (0.25–1.14) 0.10 0.13

Death 2 (3%) 1 (1%) 5.0 (0.15–157.7) 0.36 0.62

Myocardial infarction 4 (5%) 9 (12%) 0.4 (0.12–1.3) 0.13 0.13

Unstable angina 5 (7%) 9 (12%) 0.53 (0.17–1.63) 0.27 0.23

Entire follow-up

Duration, d, mean (range) 557 (180–924) 552 (138–920) 0.75‡

All cardiovascular events 16 (22%) 27 (36%) 0.49 (0.26–0.92) 0.03 0.038

Death 4 (5%) 0 (0%)§ NA NA 0.07

Myocardial infarction 5 (7%) 14 (20%) 0.27 (0.09–0.76) 0.01 0.02

Unstable angina 5 (7%) 11 (15%) 0.41 (0.14–1.22) 0.11 0.09

Stroke 2 (3%) 2 (3%) 0.69 (0.9–5.1) 0.7 0.8

Peripheral critical ischemia 0 (0%) 0 (0%) NA NA 1.0

RR indicates risk ratio; NA, not applicable.*P value obtained from Cox regression model.†P value obtained from log-rank test.‡t test.§One death due to cancer was not considered as a cardiovascular end point.

Figure 2. Kaplan-Meier plot of cumulative survival during follow-up. P value of log-rank test is calculated for secondary compos-ite end point of death, myocardial infarction, unstable angina,and stroke. P�0.038, log-rank test.

TABLE 4. Revascularizations During Both the Trialand Follow-Up

Clarithromycin(n�74)

Placebo(n�74)

During 3-month treatment

CABG 9 11

PTCA 8 10

PTCA�CABG 0 1

PTCA�2 0 4

After 3-month treatment

CABG 6 7

PTCA 4 2

PTCA�CABG 0 3

PTCA�2 0 0

Total during entire trial 27 38

PTCA�2 indicates 2 PTCA procedures.

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curves suggest that the beneficial effect starts during treat-ment and increases thereafter, with no signs of loss of effectoccurring during follow-up. Because this treatment was givenin addition to the well-managed cardiovascular medicaltherapy given to participants, the magnitude of the effect wassubstantial and comparable to that of cholesterol-loweringagents.15

Only 1 study with clinical end points and antibiotictreatment in patients with unstable angina has been publishedpreviously.7 In the ROXIS study (Roxithromycin IschemicStudy), patients appeared to benefit from 1-month macrolidetreatment. However, no benefit was seen 6 months later.According to the investigators, this could have been becauseof an insufficiently long treatment or reinfection with Chla-mydia pneumoniae.11 Compared with the ROXIS trial, thepresent study included more patients with first-time anginapectoris and fewer patients with previous myocardial infarc-tions or revascularizations. The patient population in thepresent study was also slightly older and included morewomen and more hypercholesterolemic individuals. The pri-mary end points in these 2 studies were similar; however, theROXIS trial excluded patients using antibiotics or who had arevascularization done during the trial. The treatment periodand follow-up period in the present study were 3 times longer.When the numbers of end points that occurred during the first3 months in the placebo groups are compared (26% in thepresent study versus 13% in the ROXIS trial), our studypopulation probably was more unstable. Furthermore, differ-ences were present in the patients’ normal medication: only60% of the ROXIS population but 95% of patients in thepresent study used aspirin. Together, these variances mayhave contributed to the difference in results.

Two studies with clinical end points and antibiotic treat-ment in patients with stable CAD have been published. Thefirst showed that short-term treatment could decrease epi-sodes of unstable angina or myocardial infarction.6 However,the second, larger study could not reproduce this result.8 Onecan speculate that because the patients in these studies hadstable CAD, the atherosclerotic plaques in the arteries werealso inactive, and there may have been less infectious activityin these patients. In addition, these studies included onlypatients with elevated C pneumoniae antibody titers. Thecorrelation between C pneumoniae antibodies and its occur-rence in coronary arteries is poor.3,16

We consider the antibacterial effect to be the most likelymechanism of action of clarithromycin in the present study.Animal models suggest that persistent C pneumoniae infec-tion of vessels can lead to inflammatory changes, andhypercholesterolemia may accelerate lesion progression.17

C pneumoniae is by no means the only infection associatedwith CAD. Several respiratory tract infections, viruses, anddental infections3,18,19 may also play a role. Therefore, thedrug may have influenced other infections as well. However,clarithromycin also has an anti-inflammatory effect,20 whichmay have contributed to the beneficial effect seen in thepresent study.

The time course of the treatment effect may have importantimplications for future studies. In acute infections, the benefitof antibiotics is usually seen within a few days, in contrast to

chronic infections, including C pneumoniae and periodontitis,in which healing or suppression of infection may be muchslower. In the present study, the benefit of the 3-monthtreatment was sustained for at least 1.5 years. These resultsare consistent with the reduction in an inflammatory param-eter, C-reactive protein, reported to take place only after 3months of macrolide therapy in coronary heart disease pa-tients.21 Another anti-inflammatory and plaque-stabilizingproduct, the statins, show a delayed impact on CAD, begin-ning at �1 year of therapy.15

With regard to potential sources of bias in the presentstudy, the definition of the secondary end point was revisedduring the study. The difference in the event rates betweenthe clarithromycin and placebo groups was statistically sig-nificant only for this end point. However, the revision ofend-point criteria and all assessments of coronary events weredone before treatment codes were opened. Moreover, thestudy groups were well balanced with regard to factors thatcould influence results. Substantial confounding by thesevariables is therefore unlikely to explain the results. Webelieve our findings reliably reflect the true biological effectof clarithromycin. The result is clear: the reduction in the riskof events was substantial, and only 7 patients would need tobe treated to prevent 1 cardiovascular event.

Thus, patients with acute non–Q-wave coronary syndromesappear to benefit from antibiotic treatment. This observationjustifies and warrants further studies in this field.

AppendixThe following investigators and institutions, listed in alphabeticalorder according to city (all located in Finland), participated in theCLARIFY study (number of patients enrolled in each center isshown in parentheses): Jorvi Hospital, Espoo—S. Isosomppi (12);Helsinki University Central Hospital, Helsinki—J. Sinisalo, H.Vuorinen-Markkola (32); Malmi City Hospital, Helsinki—A. Koh-vakka (10); Maria City Hospital, Helsinki —J. Sinisalo (6); Jyväs-kylä Central Hospital, Jyväskylä—J. Melin (32); Kajaani CentralHospital, Kajaani—J. Juvonen, P. Alatalo (20); Lahti Central Hos-pital, Lahti—O. Anttonen (30); Lappeenranta Central Hospital,Lappeenranta—J. Hartman (1); Turku University Central Hospital,Turku—J. Lund, M. Pietilä, L.-M. Voipio-Pulkki (5).

Steering CommitteeM.S. Nieminen (chair), J. Sinisalo (principal investigator), K. Mattila(project statistician), V. Valtonen, J. Juvonen, J. Melin, O. Anttonen,H. Vuorinen-Markkola, S. Asikainen, P. Saikku.

Writing CommitteeJ. Sinisalo, K. Mattila, V. Valtonen, J. Juvonen, J. Melin, O.Anttonen, H. Vuorinen-Markkola, M.S. Nieminen.

AcknowledgmentsThis study was supported in part by the Aarno Koskelo Foundationand the Finnish Foundation for Cardiovascular Research. AbbottLaboratories provided the trial medication and partially fundedpatient visit costs. The authors greatly appreciate the technicalassistance of Mervi Pietilä.

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Groupfor the Clarithromycin in Acute Coronary Syndrome Patients in Finland (CLARIFY) Study

Helena Vuorinen-Markkola and Markku S. NieminenJuha Sinisalo, Kimmo Mattila, Ville Valtonen, Olli Anttonen, Jukka Juvonen, John Melin,

Q-Wave Coronary Syndrome−Effect of 3 Months of Antimicrobial Treatment With Clarithromycin in Acute Non

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2002 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/01.CIR.0000012544.07696.1F

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